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D-limonene

How It Works

Bottom Line: So far, clinical trials show that d-limonene is NOT an effective cancer treatment.

D-limonene is derived from the peels of citrus fruits. Scientists are not exactly sure how it works, but it has shown anti-cancer activity in several laboratory studies. These studies suggest that D-limonene alters the signaling pathways within cancer cells in a way that halts the cancer cells as they divide and causes their death (apoptosis). In animals, D-limonene is able to slow the growth of pancreatic, stomach, colon, skin, and liver cancers. It has also shown the ability to slow the initial promotion of tumors and/or their progression in animals that have been exposed to carcinogens (cancer-causing substances). However, these anticancer effects have not been replicated in humans.

Purported Uses

  • To prevent and treat cancer
    Laboratory and animal studies show anti-cancer activity, but preliminary clinical trials do not support this use.

Research Evidence

Cancer treatment:
Researchers conducted a two-part study to assess the effectiveness of D-limonene in treating solid tumors that had not responded to other therapies. In the first part, 32 patients with solid tumors received a range of doses of intravenous D-limonene in order to identify how high the doses could go without causing toxic side effects. Because one breast cancer patient showed a partial response (shrinkage of her tumor), ten additional breast cancer patients were added to the study and were given 8 g/m2/day of D-limonene. However, none of these patients showed any tumor shrinkage. This small study does not support d-limonene as a cancer treatment.

Warnings

  • This product is regulated by the F.D.A. as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.

Side Effects

  • Nausea
  • Vomiting
  • Diarrhea
  • Allergic skin rash

Scientific Name

p-mentha-1,8-diene

Common Name

R-limonene, orange peel oil, citrus peel oil, citrene

Clinical Summary

Derived from the peels of citrus fruits. Patients use this supplement to prevent and treat cancer. D-Limonene is a cyclic monoterpene that causes G1 cell cycle arrest, induces apoptosis, and inhibits posttranslational modification of signal transduction proteins. Following oral administration, D-limonene is rapidly metabolized to limonene-1,2-diol, perillic acid, dihydroperillic acid, and uroterpenol (1) (2) (10). D-Limonene has a biologic half-life of approximately 24 hours, while its metabolites exhibit relatively short biologic half-lives of approximately 2 hours (5). Side effects include nausea, vomiting, and diarrhea (1). A case report of contact dermatitis (12) has also been reported. In vitro and animal data suggest potential efficacy of D-limonene in treating cancer, but human data are lacking. Further research is necessary to determine if D-limonene has a role in the prevention or treatment of cancer.

Purported uses

  • Cancer prevention
  • Cancer treatment

Constituents

  • Monocyclic monoterpene

Mechanism of Action

The exact mechanism of action is unknown. D-Limonene and its metabolites, perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol, may inhibit tumor growth via inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway (4) (8). D-Limonene metabolites also cause G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes (6). Animal studies show activity of D-limonene against pancreatic, stomach, colon, skin, and liver cancers (3). Data also indicate that D-limonene slows the promotion/progression stage of carcinogen-induced tumors in rats (9) (11).

Pharmacokinetics

Following oral administration, D-limonene is absorbed rapidly and metabolized to perillic acid (PA), dihydroperillic acid (DPA), limonene1,2-diol, and uroterpenol. D-Limonene metabolites distribute throughout the body to all sites, including adipose tissue, and are eliminated as glucuronide metabolites in the urine (1) (2) (10).

Adverse Reactions

Reported: Nausea, vomiting, diarrhea (1)
Case Report: Contact Dermatitis (12)

Herb-Drug Interactions

None known

Literature Summary and Critique

Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer Chemother Pharmacol 1998;42:111-7.
A phase I pharmacokinetic study was conducted with doses ranging from 500-12000 mg/m2/day. A single tumor response was documented in a breast cancer patient at the 8000 mg/m2/day dose level. The investigators conducted a small phase II study with 10 additional breast cancer patients but no additional tumor response was noted. Side effects include nausea, vomiting, and diarrhea. Additional studies are necessary to establish efficacy of D-limonene.

References

  1. Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-7.
  2. Hardcastle IR, et al. Inhibition of protein prenylation by metabolites of limonene. Biochem Pharmacol 1999;57:801-9.
  3. Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.
  4. Hudes GR, et al. Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 2000;6:3071-80.
  5. Ripple GH. Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 2000;6:390-6.
  6. Reddy BS, et al. Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 1997;57:420-5.
  7. Low-Baselli A, et al. Failure to demonstrate chemoprevention by the monoterpene perillyl alcohol during early rat hepatocarcinogenesis: a cautionary note. Carcinogenesis 2000;21:1869-77.
  8. Kaji I, et al. Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association. Int J Cancer 2001;93:441-4.
  9. Uedo N, et al. Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett 1999;137:131-6.
  10. Crowell PL, et al. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 1994;35:31-7.
  11. Asamoto M, et al. Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment. Jpn J Cancer Res 2002;93:32-5.
  12. Topham EJ, Wakelin SH. D-Limonene contact dermatitis from hand cleansers. Contact Dermatitis. 2003 Aug;49(2):108-9.

Last Updated: Sep. 18, 2007
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